The number of organ transplants performed in the United States is approximately 19,000 annually and consists predominantly of kidney transplants (11,000), liver transplants (3,600), heart transplants (2,300), and smaller numbers of pancreas, lung, heart-lung and intestinal transplants. Since 1989 when the United Network for Organ Sharing began keeping national statistics, approximately 190,000 organ transplants have been performed in the United States. A large but difficult to ascertain number of transplants were performed in the United States prior to 1989 and a similarly large number of transplants are performed in Europe and Australia and a smaller number in Asia.
Transplant tolerance remains an elusive goal for patients and physicians whose ideal would be to see a successful, allogeneic organ transplant performed without the need for indefinite, non-specific maintenance immunosuppressive drugs and their attendant, side effects. Over the past 10 years the majority of these patients have been treated with cyclosporin, azathioprine, and prednisone with a variety of other immunosuppressive agents being used as well for either induction or maintenance immunosuppression. The average annual cost per patient of maintenance immunosuppressive therapy in the United States is approximately $30,000. While the efficacy of these agents in preventing rejection is good, the side effects of immunosuppressive therapy are considerable because the unresponsiveness which they induce is nonspecific. For example, recipients can become very susceptible to infection and malignancy. Most known immunosuppressive therapies serve only to delay graft rejection and never lead to tolerance induction (12, 24) in “high responder” individuals, although some tolerance in “low responder” individuals has been reported (25, 26). A major goal in transplant immunobiology is the development of specific immune tolerance to organ transplants with the potential of freeing patients from the side effects of continuous pharmacological immunosuppression and its related complications and costs. Immune tolerance would also be of clinical significance in treatment of autoimmune diseases. In this sense immune tolerance is intended to mean the specific loss of lymphocyte reactivity to the antigen (eg. a donor allo- or xeno-antigen or an autoantigen). Although not necessarily correlating to an in vivo tolerance an in vitro analysis may be conducted as an indicator of in vivo tolerance.
Anti-T cell therapy (anti-lymphocyte globulin) has been used in rodents in conjunction with thymic injection of donor cells (Posselt et al. Science 1990; 249: 1293-1295 and Remuzzi et al. Lancet 1991; 337: 750-752). Thymic tolerance has proved successful in rodent models and involves the exposure of the recipient thymus gland to donor alloantigen prior to an organ allograft from the same donor. However, thymic tolerance has never been reported in large animals, and its relevance to tolerance in humans is unknown.
One approach to try to achieve such immunosuppression has been to expose the recipient to cells from the donor prior to the transplant, with the hope of inducing tolerance to a later transplant. This approach has involved placement of donor cells (e.g. bone marrow) presenting MHC Class 1 antigens in the recipient's thymus shortly after application of anti-lymphocyte serum (ALS) or radiation. However, this approach has proved difficult to adapt to live primates (e.g. monkeys; humans). ALS and/or radiation render the host susceptible to disease or side-effects and/or are insufficiently effective.
Autoimmune diseases represent a major public health problem. The autoimmune disease, type I diabetes is mediated by CD8+ T cells mediated injury to the beta cells of the pancreas, multiple sclerosis is probably mediated by both CD4+ T cells and CD8+ T cells and rheumatoid arthritis is a immune inflammatory disease in which CD4+ T cells play a central role. Glomerulonephritis is dependent upon CD4+ T cell activation and mediated by CD8+ T cells, which in experimental models can be regulated by suppressor T cells. Other auto-immune diseases affect a smaller proportion of patients but carry a significant disease burden and include myasthenia gravis, chronic inflammatory demyelinating neuropathy, inflammatory bowel disease, chronic active hepatitis, interstitial pneumonitis, dermatomyositis and systemic lupus erythematosis. The incidence of multiple sclerosis in the Western world is up to 60/100,000, total patients 3.6 million. Type I diabetes affects 0.25% of young people (30 million affected, 1.5 million new patients per year). Rheumatoid arthritis affects approximately 1% of the population or 6 million people in Western countries. Current therapies only aim to control disease activity by suppressing inflammation. Regular immunosuppressive drugs such as prednisone, azathioprine and cyclophosphamide will control diseases such as nephritis but do not always induce tolerance. More recently, newer immunosuppressive drugs have been used with some effect, including cyclosporine, FK506 and mycophenolate mofetil. In multiple sclerosis beta interferon and cepaxone a copolymer will reduce relapse rates but do not restore tolerance. Still further autoimmune diseases include asthma and the dermatological diseases psoriasis and atopic dermatitis.
T cell derived cytokines are thought to be mediators of induction and maintenance of immune mediated tolerance, but the precise cytokines involved are not known. The primary effectors of rejection are Th1 cells producing IL-2, IFN-γ, and TNF-α, whilst Th2 cells producing IL-4, IL-10 have been implicated as regulator cells that inhibit Th1 cells and facilitate induction of tolerance (1-3). IL-4 and IL-10 have been extensively studied and have been reported to either accelerate rejection or prolong graft survival (4-9). IL-5 is an inducible glycoprotein cytokine produced mainly by activated T cells in response to antigenic or allergic stimulation. IL-5 promotes eosinophil and basophil growth, is a major inflammatory mediator in asthma and other allergic diseases and has a role in defence against parasitic infection (10). Its predominant effect is on eosinophil and basophil activation and proliferation. IL-5 also acts on B cells facilitating IgG isotype switching to IgG1 and IgE (10). IL-5 acts on target cells through interaction with a specific IL-5 receptor composed of an IL-5 ligand binding alpha-subunit and a non-ligand binding beta-subunit that is shared by the receptors for IL-3 and GM-CSF. Expression of IL-5 receptors is restricted to eosinophils and basophils. IL-5 has no known direct effect on T cells, which lack the alpha receptor for IL-5 (10).
A reliable and safe approach to immunologic tolerance would be of tremendous value and appeal to autoimmune disease and transplant recipient patients and their physicians. Such an approach would have immediate application to autoimmune disease treatment and to treatment of patients with new organ transplants. There is also potential application to patients with existing transplants, with stable transplant function.